tbuckley/cabot-search huggingface dataset:
Engineered Microbial Nanohybrids for Tumor‐Mediated NIR II Photothermal Enhanced Ferroptosis/Cuproptosis and Immunotherapy
Authors: Yihang Ruan, Huilan Zhuang, Xuemei Zeng, Lili Lin, Xuechun Wang, Panpan Xue, Shan Xu, Qi Chen, Shuangqian Yan, Wei Huang
Journal: Advanced Healthcare Materials (2023)

Abstract The colon tumor microenvironment has a high concentration of H 2 S and glutathione, which is highly immunosuppressive and adverse to multiple therapeutic methodologies such as ferroptosis. Here, an engineered microbial nanohybrid based on Escherichia coli ( E. coli ) and Cu 2 O nanoparticles to specific colon tumor therapy and immunosuppression reversion is reported. The as‐prepared E. coli @Cu 2 O hybrid can accumulate in tumor sites upon intravenous injection, and Cu 2 O nanoparticles convert to Cu x S by consuming the endogenous H 2 S, which exhibits strong photothermal conversion at near‐infrared II (NIR II) biological window. Furthermore, E. coli @Cu 2 O is able to induce cellular ferroptosis and cuproptosis through inactivation of glutathione peroxidase 4 and aggregation of dihydrolipoamide S‐acetyltransferase, respectively. Photothermal‐enhanced ferroptosis/cuproptosis achieved by E. coli @Cu 2 O reverses the immunosuppression of colon tumors by triggering dendritic cell maturation (about 30%) and T cell activation (about 50% CD8 + T cells). Concerted with immune checkpoint blockade, the engineered microbial nanohybrid can inhibit the growth of abscopal tumors upon NIR illumination. Overall, the designed microbial nanohybrid can achieve tumor‐specific photothermal‐enhanced ferroptosis/cuproptosis and immunosuppression reversion, showing promise in precise tumor therapy in future clinical translation.
Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1–Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial
Authors: Martin Reck, Fabrice Barlesi, James Chih-Hsin Yang, Virginie Westeel, Enriqueta Felip, Mustafa Özgüroğlu, Manuel Cobo Dols, Richard Sullivan, Dariusz M. Kowalski, Zoran Andric, Dae Ho Lee, Ahmet Sezer, Ping Hu, XiaoZhe Wang, Anja von Heydebreck, Natalia Jacob, Keyvan Tadjalli Mehr, Keunchil Park
Journal: Journal of Thoracic Oncology (2023)

Introduction:We report the primary analysis from JAVELIN Lung 100, a phase 3 trial comparing avelumab (anti -PD-L1) vs platinum-based doublet chemotherapy as first-line treatment for PD-L1+ advanced non-small cell lung cancer (NSCLC).Methods: Adults with PD-L1+ (≥1% of tumor cells; PD-L1 IHC 73-10 pharmDx), EGFR/ALK-wild-type, previously untreated, stage IV NSCLC were randomized to avelumab 10 mg/kg every 2 weeks (Q2W), avelumab 10 mg/kg once weekly (QW) for 12 weeks and Q2W thereafter, or platinum-based doublet chemotherapy every 3 weeks.Primary endpoints were overall survival (OS) and progression-free survival (PFS) per independent review committee.The primary analysis population was patients with high-expression PD-L1+ tumors (≥80% of tumor cells).Results: 1214 patients were randomized to avelumab Q2W (n=366), avelumab QW (n=322), or chemotherapy (n=526).In the primary analysis population, hazard ratios (HRs) for OS and PFS with avelumab Q2W (n=151) vs chemotherapy (n=216) were 0.85 ([95% CI, 0.67-1.09];1-sided p=0.1032; median OS, 20.1 vs 14.9 months), and 0.71 ([95% CI, 0.54-0.93];1-sided p=0.0070; median PFS, 8.4 vs 5.6 months), respectively.With avelumab QW (n=130) vs chemotherapy (n=129), HRs were 0.79 ([95% CI, 0.59-1.07];1-sided p=0.0630; median OS, 19.3 vs 15.3 months) and 0.72 ([95% CI, 0.52-0.98];1-sided p=0.0196; median PFS, 7.5 vs 5.6 months), respectively.No new safety signals were observed.Conclusions: Longer median OS and PFS were observed with avelumab vs platinum-based doublet chemotherapy in advanced NSCLC, but differences in OS and PFS were not statistically significant, and the trial did not meet its primary objective. ClinicalTrials.gov
FGFR families: biological functions and therapeutic interventions in tumors
Authors: Qing Liu, Jiyu Huang, Weiwei Yan, Zhen Liu, Shu Liu, Weiyi Fang
Journal: MedComm (2023)

Abstract There are five fibroblast growth factor receptors (FGFRs), namely, FGFR1–FGFR5. When FGFR binds to its ligand, namely, fibroblast growth factor (FGF), it dimerizes and autophosphorylates, thereby activating several key downstream pathways that play an important role in normal physiology, such as the Ras/Raf/mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase, phosphoinositide 3‐kinase (PI3K)/AKT, phospholipase C gamma/diacylglycerol/protein kinase c, and signal transducer and activator of transcription pathways. Furthermore, as an oncogene, FGFR genetic alterations were found in 7.1% of tumors, and these alterations include gene amplification, gene mutations, gene fusions or rearrangements. Therefore, FGFR amplification, mutations, rearrangements, or fusions are considered as potential biomarkers of FGFR therapeutic response for tyrosine kinase inhibitors (TKIs). However, it is worth noting that with increased use, resistance to TKIs inevitably develops, such as the well‐known gatekeeper mutations. Thus, overcoming the development of drug resistance becomes a serious problem. This review mainly outlines the FGFR family functions, related pathways, and therapeutic agents in tumors with the aim of obtaining better outcomes for cancer patients with FGFR changes. The information provided in this review may provide additional therapeutic ideas for tumor patients with FGFR abnormalities.
Expansion of Pathogenic Cardiac Macrophages in Immune Checkpoint Inhibitor Myocarditis
Authors: Pan Ma, Jing Liu, Juan Qin, Lulu Lai, Gyu Seong Heo, Hannah Luehmann, Deborah Sultan, Andrea Bredemeyer, Geetika Bajapa, Guoshuai Feng, Jesus Jimenez, Ruijun He, Antanisha Parks, Junedh Amrute, Ana Villanueva, Yongjian Liu, Chieh-Yu Lin, Matthias Mack, Kaushik Amancherla, Javid Moslehi, Kory J. Lavine
Journal: Circulation (2023)

Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages.
Gut virome profiling identifies an association between temperate phages and colorectal cancer promoted by <i>Helicobacter pylori</i> infection
Authors: Shiqi Luo, Jinlong Ru, Mohammadali Khan Mirzaei, Jinling Xue, Xue Peng, Anna Ralser, Raquel Mejías-Luque, Markus Gerhard, Li Deng
Journal: Gut Microbes (2023)

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While a close correlation between chronic Helicobacter pylori infection and CRC has been reported, the role of the virome has been overlooked. Here, we infected Apc-mutant mouse models and C57BL/6 mice with H. pylori and conducted a comprehensive metagenomics analysis of H. pylori-induced changes in lower gastrointestinal tract bacterial and viral communities. We observed an expansion of temperate phages in H. pylori infected Apc+/1638N mice at the early stage of carcinogenesis. Some of the temperate phages were predicted to infect bacteria associated with CRC, including Enterococcus faecalis. We also observed a high prevalence of virulent genes, such as flgJ, cwlJ, and sleB, encoded by temperate phages. In addition, we identified phages associated with pre-onset and onset of H. pylori-promoted carcinogenesis. Through co-occurrence network analysis, we found strong associations between the viral and bacterial communities in infected mice before the onset of carcinogenesis. These findings suggest that the expansion of temperate phages, possibly caused by prophage induction triggered by H. pylori infection, may have contributed to the development of CRC in mice by interacting with the bacterial community.
Error in Author Degrees
Journal: JAMA Pediatrics (2023)

Joseph L. Ward, PhD; Rachel Harwood, PhD; Simon Kenny, MD; Joana Cruz, PhD; Matthew Clark, MB, BChir; Peter J. Davis, MB, ChB; Elizabeth S. Draper, PhD; Dougal Hargreaves, MD (Res); Shamez N. Ladhani, PhD; Nick Gent, MB, ChB; Hannah E. Williams, PhD; Karen Luyt, PhD; Steve Turner, MD; Elizabeth Whittaker, PhD; Alex Bottle, PhD; Lorna K. Fraser, PhD; Russell M. Viner, PhD
<i>In Utero</i> Exposure to Metals and Birth Outcomes in an Artisanal and Small-Scale Gold Mining Birth Cohort in Madre de Dios, Peru
Authors: Axel J. Berky, Caren Weinhouse, Joao Vissoci, Nelson Rivera, Ernesto J. Ortiz, Susy Navio, J. Jaime Miranda, Andres Mallipudi, Emma Fixen, Heileen Hsu-Kim, William K. Pan
Journal: Environmental Health Perspectives (2023)

Few birth cohorts in South America evaluate the joint effect of minerals and toxic metals on neonatal health. In Madre de Dios, Peru, mercury exposure is prevalent owing to artisanal gold mining, yet its effect on neonatal health is unknown.
Direct Mapping of Cytomechanical Homeostasis Destruction in Osteoarthritis Based on Silicon Nanopillar Array
Authors: Dengjie Yu, Qingbin Nie, Jiangtao Xue, Ruizeng Luo, Shiwang Xie, Shengyu Chao, Engui Wang, Linlin Xu, Yizhu Shan, Zhuo Liu, Yusheng Li, Zhou Li
Journal: Advanced Healthcare Materials (2023)

Osteoarthritis (OA) is the most prevalent joint degenerative disease characterized by chronic joint inflammation. The pathogenesis of OA has not been fully elucidated yet. Cartilage erosion is the most significant pathological feature in OA, which is considered the result of cytomechanical homeostasis destruction. The cytomechanical homeostasis is maintained by the dynamic interaction between cells and the extracellular matrix, which can be reflected by cell traction force (CTF). It is critical to assess the CTF to provide a deeper understanding of the cytomechanical homeostasis destruction and progression in OA. In this study, a silicon nanopillar array (Si-NP) with high spatial resolution and aspect ratio is fabricated to investigate the CTF in response to OA. It is discovered that the CTF is degraded in OA, which is attributed to the F-actin reorganization induced by the activation of RhoA/ROCK signaling pathway. Si-NP also shows promising potential as a mechanopharmacological assessment platform for OA drug screening and evaluation.
White Matter Tract Density Index Prediction Model of Overall Survival in Glioblastoma
Authors: Alessandro Salvalaggio, Lorenzo Pini, Matteo Gaiola, Aron Velco, Giulio Sansone, Mariagiulia Anglani, Lucius Fekonja, Franco Chioffi, Thomas Picht, Michel Thiebaut de Schotten, Vittorina Zagonel, Giuseppe Lombardi, Domenico D’Avella, Maurizio Corbetta
Journal: JAMA Neurology (2023)

The prognosis of overall survival (OS) in patients with glioblastoma (GBM) may depend on the underlying structural connectivity of the brain.To examine the association between white matter tracts affected by GBM and patients' OS by means of a new tract density index (TDI).This prognostic study in patients with a histopathologic diagnosis of GBM examined a discovery cohort of 112 patients who underwent surgery between February 1, 2015, and November 30, 2020 (follow-up to May 31, 2023), in Italy and 70 patients in a replicative cohort (n = 70) who underwent surgery between September 1, 2012, and November 30, 2015 (follow-up to May 31, 2023), in Germany. Statistical analyses were performed from June 1, 2021, to May 31, 2023. Thirteen and 12 patients were excluded from the discovery and the replicative sets, respectively, because of magnetic resonance imaging artifacts.The density of white matter tracts encompassing GBM.Correlation, linear regression, Cox proportional hazards regression, Kaplan-Meier, and prediction analysis were used to assess the association between the TDI and OS. Results were compared with common prognostic factors of GBM, including age, performance status, O6-methylguanine-DNA methyltransferase methylation, and extent of surgery.In the discovery cohort (n = 99; mean [SD] age, 62.2 [11.5] years; 29 female [29.3%]; 70 male [70.7%]), the TDI was significantly correlated with OS (r = -0.34; P < .001). This association was more stable compared with other prognostic factors. The TDI showed a significant regression pattern (Cox: hazard ratio, 0.28 [95% CI, 0.02-0.55; P = .04]; linear: t = -2.366; P = .02). and a significant Kaplan-Meier stratification of patients as having lower or higher OS based on the TDI (log-rank test = 4.52; P = .03). Results were confirmed in the replicative cohort (n = 58; mean [SD] age, 58.5 [11.1] years, 14 female [24.1%]; 44 male [75.9%]). High (24-month cutoff) and low (18-month cutoff) OS was predicted based on the TDI computed in the discovery cohort (accuracy = 87%).In this study, GBMs encompassing regions with low white matter tract density were associated with longer OS. These findings indicate that the TDI is a reliable presurgical outcome predictor that may be considered in clinical trials and clinical practice. These findings support a framework in which the outcome of GBM depends on the patient's brain organization.
Childhood and Adolescence Gender Role Nonconformity and Gender and Sexuality Diversity in Young Adulthood
Authors: Jennifer L. Marino, Ashleigh Lin, Cristyn Davies, Melissa Kang, Sarita Bista, S. Rachel Skinner
Journal: JAMA Pediatrics (2023)

Sexuality- and gender-diverse youth experience disproportionate health and social adversity. Accurate early-life indicators are important for development of supportive approaches.
EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes
Authors: Yeying Huang, R. Taylor Durall, Nhi M. Luong, Hans J. Hertzler, Julianna Huang, Prafulla C. Gokhale, Brittaney A. Leeper, Nicole S. Persky, David E. Root, Praju V. Anekal, Paula D.L.M. Montero Llopis, Clement N. David, Jeffery L. Kutok, Alejandra Raimondi, Karan Saluja, Jia Luo, Cynthia A. Zahnow, Biniam Adane, Kimberly Stegmaier, Catherine E. Hawkins, Christopher Ponne, Quan Le, Geoffrey I. Shapiro, Madeleine E. Lemieux, Kyle P. Eagen, Christopher A. French
Journal: Cancer Research (2023)

NUT carcinoma is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of progrowth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NUT carcinoma that can impede BRD4-NUT's ability to activate genes, but the efficacy of BETi as monotherapy is limited. Here, we demonstrated that enhancer of zeste homolog 2 (EZH2), which silences genes through establishment of repressive chromatin, is a dependency in NUT carcinoma. Inhibition of EZH2 with the clinical compound tazemetostat potently blocked growth of NUT carcinoma cells. Epigenetic and transcriptomic analysis revealed that tazemetostat reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4-NUT-regulated genes. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NUT carcinoma cells. CDKN2A was identified as the only gene among all tazemetostat-derepressed genes to confer resistance to tazemetostat in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes, resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In preclinical models, combined tazemetostat and BETi synergistically blocked tumor growth and prolonged survival of NUT carcinoma-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NUT carcinoma substantiates the reliance of NUT carcinoma tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NUT carcinoma growth.
Lipophilic AIEgens as the “Trojan Horse” with Discrepant Efficacy in Tracking and Treatment of Mycobacterial Infection
Authors: Chunzi Shi, Xueni Huang, Dong Wang, Chengshengze Chu, Yuxin Shi, Bo Yan, Fei Shan, Jiulong Zhang, Zhiyong Zhang, Chen Peng, Ben Zhong Tang
Journal: Advanced Healthcare Materials (2023)

Abstract The highly contagious tuberculosis is a leading infectious killer, which urgently requires effective diagnosis and treatment methods. To address these issues, three lipophilic aggregation‐induced emission (AIE) photosensitizers (TTMN, TTTMN, and MeOTTMN) are selected to evaluate their labeling and antimicrobial properties in vitro and in vivo. These three lipophilic AIEgens preserve low cytotoxicity and achieve real‐time and non‐invasive visualization of the process of mycobacteria infection in vitro and in vivo. More importantly, these AIEgens can be triggered by white light to produce reactive oxygen species (ROS), which is a highly efficient antibacterial reagent. Among these AIEgens, the TTMN photosensitizer has an outstanding antibacterial efficacy over the clinical first‐line drug rifampicin at the same therapeutic concentration. Interestingly, this study also finds that TTMN can increase the expression of pro‐inflammatory cytokines in the early stage of infection after light irradiation, indicating an additional pro‐inflammatory role of TTMN. This work provides some feasibility basis for developing AIEgens‐based agents for effectively destroying mycobacterium.
Cross-talk between PARN and EGFR–STAT3 Signaling Facilitates Self-Renewal and Proliferation of Glioblastoma Stem Cells
Authors: Jinlong Yin, Yoona Seo, Jiho Rhim, Xiong Jin, Tae Hoon Kim, Sung Soo Kim, Jun-Hee Hong, Ho-Shin Gwak, Heon Yoo, Jong Bae Park, Jong Heon Kim
Journal: Cancer Research (2023)

Abstract Glioblastoma is the most common type of malignant primary brain tumor and displays highly aggressive and heterogeneous phenotypes. The transcription factor STAT3 has been reported to play a key role in glioblastoma malignancy. Thus, discovering targets and functional downstream networks regulated by STAT3 that govern glioblastoma pathogenesis may lead to improved treatment strategies. In this study, we identified that poly(A)-specific ribonuclease (PARN), a key modulator of RNA metabolism, activates EGFR–STAT3 signaling to support glioblastoma stem cells (GSC). Functional integrative analysis of STAT3 found PARN as the top-scoring transcriptional target involved in RNA processing in patients with glioblastoma, and PARN expression was strongly correlated with poor patient survival and elevated malignancy. PARN positively regulated self-renewal and proliferation of GSCs through its 3′–5′ exoribonuclease activity. EGFR was identified as a clinically relevant target of PARN in GSCs. PARN positively modulated EGFR by negatively regulating the EGFR-targeting miRNA miR-7, and increased EGFR expression created a positive feedback loop to increase STAT3 activation. PARN depletion in GSCs reduced infiltration and prolonged survival in orthotopic brain tumor xenografts; similar results were observed using siRNA nanocapsule-mediated PARN targeting. Pharmacological targeting of STAT3 also confirmed PARN regulation by STAT3 signaling. In sum, these results suggest that a STAT3-PARN regulatory network plays a pivotal role in tumor progression and thus may represent a target for glioblastoma therapeutics. Significance: A positive feedback loop comprising PARN and EGFR–STAT3 signaling supports self-renewal and proliferation of glioblastoma stem cells to drive tumor progression and can be targeted in glioblastoma therapeutics.
The SeLECT 2.0 Score—Significance of Treatment With Antiseizure Medication—Reply
Authors: Kai Michael Schubert, Lucia Sinka, Marian Galovic
Journal: JAMA Neurology (2023)

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Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis
Authors: Nicholas Jex, John P. Greenwood, Richard M. Cubbon, Oliver J. Rider, Amrit Chowdhary, Sharmaine Thirunavukarasu, Sindhoora Kotha, Marilena Giannoudi, Anna McGrane, Amanda Maccannell, Marcella Conning-Rowland, Sam Straw, Henry Procter, Sotiris Papaspyros, Betsy Evans, Kalyana Javangula, Antonella Ferrara, Walid Elmahdy, Pankaj Kaul, Hui Xue, Peter Swoboda, Peter Kellman, Ladislav Valkovič, Lee Roberts, David Beech, Mark T. Kearney, Sven Plein, Marc R. Dweck, Eylem Levelt
Journal: Circulation (2023)

Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR.
Targeting WNT/β-Catenin via Modulating EZH2 Function: A New Chapter in the Treatment of β-Catenin Mutant Hepatocellular Carcinoma?
Authors: Man Hsin Hung, Xin Wei Wang
Journal: Cancer Research (2023)

Abstract In a recent study, Rialdi and colleagues identified a specific vulnerability in β-catenin mutant hepatocellular carcinoma (HCC) via EZH2-mediated suppression of WNT signaling and revealed the selective anti-HCC activity of WNTinib, a chemical derivative of regorafenib and sorafenib in targeting this vulnerability. Their discoveries highlight the role of EZH2 in modulating WNT signaling and suggest an implication of WNTinihb as a small-molecule inhibitor for the treatment of HCC with activated WNT/β-catenin.